scholarly journals Interstitial Lung Disease Associated with mTOR Inhibitors in Solid Organ Transplant Recipients: Results from a Large Phase III Clinical Trial Program of Everolimus and Review of the Literature

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Patricia Lopez ◽  
Sven Kohler ◽  
Seema Dimri
Keyword(s):  
Interstitial Lung Disease ◽  
Lung Disease ◽  
De Novo ◽  
Early Recognition ◽  
Mtor Inhibitors ◽  
Phase Iii ◽  
Drug Discontinuation ◽  
Solid Organ ◽  
Transplant Recipients ◽  
Phase Iii Trials

Interstitial lung disease (ILD) has been reported with the use of mammalian target of rapamycin inhibitors (mTORi). The clinical and safety databases of three Phase III trials of everolimus inde novokidney (A2309), heart (A2310), and liver (H2304) transplant recipients (TxR) were searched using a standardized MedDRA query (SMQ) search for ILD followed by a case-by-case medical evaluation. A literature search was conducted in MEDLINE and EMBASE. Out of the 1,473de novoTxR receiving everolimus in Phase III trials, everolimus-related ILD was confirmed in six cases (one kidney, four heart, and one liver TxR) representing an incidence of 0.4%. Everolimus was discontinued in three of the four heart TxR, resulting in ILD improvement or resolution. Outcome was fatal in the kidney TxR (in whom everolimus therapy was continued) and in the liver TxR despite everolimus discontinuation. The literature review identified 57 publications on ILD in solid organ TxR receiving everolimus or sirolimus. ILD presented months or years after mTORi initiation and symptoms were nonspecific and insidious. The event was more frequent in patients with a late switch to mTORi. In most cases, ILD was reversed after prompt mTORi discontinuation. ILD induced by mTORi is an uncommon and potentially fatal event warranting early recognition and drug discontinuation.

scholarly journals Impact of Lung Function Decline on Time to Hospitalisation Events in Systemic Sclerosis-associated Interstitial Lung Disease (SSc-ILD): a Joint Model Analysis

2021 ◽  
Author(s):  
Michael Kreuter ◽  
Francesco Del Galdo ◽  
Corinna Miede ◽  
Dinesh Khanna ◽  
Wim A. Wuyts ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Interstitial Lung Disease ◽  
Lung Function ◽  
Lung Disease ◽  
Fold Increase ◽  
Phase Iii ◽  
Lung Function Decline ◽  
Related Hospitalisation ◽  
The Relationship ◽  
Increase In Risk

Abstract Background: Interstitial lung disease (ILD) is a common organ manifestation in systemic sclerosis (SSc) and is the leading cause of death in patients with SSc. A decline in forced vital capacity (FVC) is an indicator of ILD progression and is associated with mortality in patients with SSc-associated ILD (SSc-ILD). However, the relationship between FVC decline and hospitalisation events in patients with SSc-ILD is largely unknown. The objective of this post-hoc analysis was to investigate the relationship between FVC decline and clinically important hospitalisation endpoints.Methods: We used data from SENSCIS®, a Phase III trial investigating the efficacy and safety of nintedanib in patients with SSc-ILD. Joint models for longitudinal and time-to-event data were used to assess the association between rate of decline in FVC% predicted and hospitalisation-related endpoints (including time to first all-cause hospitalisation or death; time to first SSc-related hospitalisation or death; and time to first admission to an emergency room [ER] or admission to hospital followed by admission to intensive care unit [ICU] or death) during the treatment period, over 52 weeks in patients with SSc-ILD.Results: There was a statistically significant association between FVC decline and the risk of all-cause (n=78) and SSc-related (n=42) hospitalisations or death (both P<0.0001). A decrease of 3% in FVC corresponded to a 1.43-fold increase in risk of all-cause hospitalisation or death (95% confidence interval [CI] 1.24, 1.65) and a 1.48-fold increase in risk of SSc-related hospitalisation or death (95% CI 1.23, 1.77). No statistically significant association was observed between FVC decline and admission to ER or to hospital followed by admission to ICU or death (n=75; P=0.15). The estimated slope difference for nintedanib versus placebo in the longitudinal sub-model was consistent with the primary analysis in SENSCIS®.Conclusions: The association of lung function decline with an increased risk of hospitalisation suggests that slowing FVC decline in patients with SSc-ILD may prevent hospitalisations. Our findings also provide evidence that FVC decline may serve as a surrogate endpoint for clinically relevant hospitalisation-associated endpoints.Trial registration: Clinialtrials.gov, NCT02597933. Registered 8 October 2015, https://clinicaltrials.gov/ct2/show/study/NCT02597933.

scholarly journals Longitudinal assessment of interstitial lung disease in single lung transplant recipients with scleroderma

Rheumatology ◽  
2019 ◽  
Vol 59 (4) ◽  
pp. 790-798
Author(s):  
Alicia M Hinze ◽  
Cheng T Lin ◽  
Amira F Hussien ◽  
Jamie Perin ◽  
Aida Venado ◽  
...  
Keyword(s):  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Lung Transplant ◽  
Transplant Recipients ◽  
Longitudinal Assessment ◽  
Hounsfield Units ◽  
Lung Density ◽  
Native Lung ◽  
Single Lung Transplant ◽  
Lung Transplant Recipients

Abstract Objective To investigate the natural history of fibrotic lung disease in recipients of a single lung transplant for scleroderma-associated interstitial lung disease (ILD). Methods Global ILD (including ground glass, nodular opacities and fibrosis) was categorized into severity quintiles on first and last post-transplant CT scans, and percent fibrosis by manual contouring was also determined, in nine single lung transplant recipients. Quantitative mean lung densities and volumes for the native and allograft lungs were also acquired. Results In the native lung, global ILD severity quintile worsened in two cases and percent fibrosis worsened in four cases (range 5–28%). In the lung allograft, one case each developed mild, moderate and severe ILD; of these, new fibrotic ILD (involving &lt;10% of lung) occurred in two cases and acute cellular rejection occurred in one. The average change in native lung density over time was +2.2 Hounsfield Units per year and lung volume +1.4 ml per year, whereas the allograft lung density changed by –5.5 Hounsfield Units per year and total volume +27 ml per year (P = 0.011 and P = 0.039 for native vs allograft density and volume comparisons, respectively). Conclusions While the course of ILD in the native and transplanted lungs varied in this series, these cases illustrate that disease progression is common in the native lung, suggesting that either the immune process continues to target autoantigens or ongoing fibrotic pathways are active in the native lung. Mild lung disease may occur in the allograft after several years due to either allograft rejection or recurrent mild ILD.

scholarly journals P1761SIDE EFFECTS OF MTOR INHIBITORS DEPEND ON THE BASELINE METABOLIC STATUS OF KIDNEY TRANSPLANT RECIPIENTS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
David Cucchiari ◽  
Alicia Molina-Andujar ◽  
Enrique Montagud-Marrahi ◽  
Jordi Rovira ◽  
Fritz Diekmann
Keyword(s):  
Kidney Transplantation ◽  
Side Effects ◽  
Kidney Transplant ◽  
De Novo ◽  
Mtor Inhibitors ◽  
Metabolic Status ◽  
Transplant Recipients ◽  
Kidney Transplant Recipients ◽  
Post Hoc Analysis ◽  
Post Hoc

Abstract Background and Aims Biologically, the cellular activity of the mTOR complexes depends on the balance between the catabolic and the anabolic inputs. Hence, we hypothesized that the metabolic side effects of mTOR inhibitors (mTORi) in kidney transplantation depend on the baseline metabolic status of the patient. Method The analysis included all the patients that have been transplanted in our Center between June 2013 to December 2016, completed one year of follow-up and did not change medication during the first year after kidney transplantation (per-protocol population, n=298). Outcomes chosen include de novo diabetes, 1-year difference from baseline in glycated hemoglobin (HbA1c), triglycerides and total cholesterol. Kidney transplant recipients were treated either with an mTORi (either Sirolimus or Everolimus, n=134) or Mycophenolic Acid (MPA, n=164). Both drugs were always accompanied by tacrolimus and steroids. Patients were stratified according to the treatment received (mTORi versus MPA) and the baseline metabolic status (diabetes mellitus type 2 and obesity). Differences among groups were analyzed with exact Fisher test and ANOVA test with LSD post-hoc analysis. Results We observed a strong difference for 1-year change in HbA1c depending on the baseline metabolic status of the patients (P&lt;0.001 between groups, Figure 1a). The worst results were observed for patients with baseline diabetes. Among these, obese patients treated with mTORi had the higher increase in HbA1c (3.04 ± 1.18% from baseline, P&lt;0.01 with all groups at post-hoc analysis). De-novo diabetes was more frequent in patients taking mTORi (23.4 vs. 13.1%), albeit not significantly (P=0.100) and without differences taking into account obesity as a covariate. Triglycerides increased substantially in patients without baseline diabetes and treated with mTORi (P&lt;0.05). Surprisingly, in diabetic patients no differences were observed in triglycerides between mTORi and MPA groups (Figure 1b). There were no differences in the increase in total cholesterol among groups (P=0.155) (Figure 1c). Conclusion We observed that the 1-year increase in HbA1c and triglycerides attributable to mTORi after kidney transplantation depends on the baseline metabolic status of the patients. We propose that the metabolic side effects of mTORi depend on the balance between anabolic and catabolic inputs of every kidney transplant recipient.

scholarly journals Diffuse Pulmonary Ossification as a Rare Cause of Interstitial Lung Disease

2014 ◽  
Vol 21 (1) ◽  
pp. 23-24 ◽  
Author(s):  
Andrew Burkett ◽  
Niamh Coffey ◽  
Nha Voduc
Keyword(s):  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Distress Syndrome ◽  
Organ Transplant ◽  
Solid Organ ◽  
Diffusing Capacity ◽  
Left Heart ◽  
Rare Form ◽  
Left Heart Failure ◽  
Progressive Dyspnea

Diffuse pulmonary ossification (DPO) is a rare form of interstitial lung disease. The present article describes a case of DPO in an elderly man who presented with progressive dyspnea on exertion and an isolated reduction in diffusing capacity for carbon monoxide. DPO may occur as sequelae of mitral stenosis, left heart failure, idiopathic pulmonary fibrosis, recurrent aspiration pneumonia, solid organ transplant, adult respiratory distress syndrome or may arise idiopathically. In the absence of other findings of interstitial lung disease, a lung biopsy is unlikely to be helpful in the management of these patients.

scholarly journals Metastatic renal cell carcinoma: Current scenario and future trends

2012 ◽  
Vol 01 (01) ◽  
pp. 30-35
Author(s):  
Anubha Bharthuar
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Mtor Inhibitors ◽  
Phase Iii ◽  
The Novel ◽  
Optimal Dosing ◽  
Phase Iii Trials ◽  
Current Scenario ◽  
Metastatic Rcc

AbstractAn improved understanding of the biology of renal cell carcinoma (RCC) has led to the development of a number of targeted agents, which has resulted in a paradigm shift in the management of metastatic RCC. We review the current therapeutic strategies for metastatic RCC and present a synopsis of the novel agents in use today with a discussion of the phase III trials that demonstrated their clinical benefit. The management of RCC continues to evolve. The introduction of VEGF and mTOR inhibitors has markedly expanded our drug armamentarium and improved the outcome of a disease that has always been challenging to treat. Knowledge from upcoming trials will help us utilize these drugs for maximum clinical efficacy with optimal dosing and sequencing, either individually or in combination therapy.

Incidence and Treatment of Cancer in Transplant Recipients

1998 ◽  
Vol 8 (2) ◽  
pp. 105-112 ◽  
Author(s):  
Maureen P. Flattery
Keyword(s):  
De Novo ◽  
Solid Organ Transplantation ◽  
Organ Transplant ◽  
Cardiac Transplant ◽  
Solid Organ ◽  
Transplant Recipients ◽  
Organ Transplant Recipients ◽  
Organ Rejection ◽  
Increased Risk ◽  
Actuarial Risk

Solid organ transplantation has been an accepted mode of therapy for the treatment of end-stage organ diseases for many years. Recipients' survival, however, has been hindered by organ rejection and the comorbid diseases that develop as a result of immunosuppressive therapy. In particular, organ transplant recipients have an increased risk of developing cancer de novo after transplantation. Prevalence ranges from 4 to 18% with an average incidence of 6%. Data submitted to the Cincinnati transplant tumor registry have revealed that cancers prevalent in the general population exhibited no increase in rate and may even show a slight decline in the transplant population. Length of survival after transplantation is associated with the likelihood of having cancer; the longer the recipient survives, the greater the chance. The actuarial risk among 124 cardiac transplant recipients was 2.7+/-1.9% at 1 year and 25.6+/-11% at 5 years. This article will review the current literature on the incidence and treatment of cancer in solid organ transplant recipients.

scholarly journals Immunotherapy for advanced hepatocellular carcinoma: a focus on special subgroups

Gut ◽  
2020 ◽  
Vol 70 (1) ◽  
pp. 204-214 ◽  
Author(s):  
Matthias Pinter ◽  
Bernhard Scheiner ◽  
Markus Peck-Radosavljevic
Keyword(s):  
Hepatocellular Carcinoma ◽  
Solid Organ Transplantation ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
The United States ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Solid Organ ◽  
United States Food ◽  
Phase Iii Trials

Following the success of immune checkpoint blockers (ICBs) in different cancer types, a large number of studies are currently investigating ICBs in patients with hepatocellular carcinoma (HCC), alone or in combination with other treatments. Both nivolumab and pembrolizumab, as well as the combination of nivolumab plus ipilimumab have been granted accelerated approval by the United States Food and Drug Administration for sorafenib-pretreated patients. While nivolumab and pembrolizumab both failed to meet their primary endpoints in phase III trials, the combination of atezolizumab plus bevacizumab eventually improved overall and progression-free survival compared with sorafenib in a front-line phase III trial, and thus, will become the new standard of care in this setting. Despite this breakthrough, there are patient populations with certain underlying conditions that may not be ideal candidates for this new treatment either due to safety concerns or potential lack of efficacy. In this review, we discuss the safety of ICBs in patients with pre-existing autoimmune disease, IBD or a history of solid organ transplantation. Moreover, we summarise emerging preclinical and clinical data suggesting that ICBs may be less efficacious in patients with underlying non-alcoholic steatohepatitis or HCCs with activated Wnt/β-catenin signalling.

Post-Renal Transplant De Novo Non-Skin Malignancies in Mycophenolate Mofetil- and Calcineurin Inhibitor-Based Immunosuppression.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1683-1683
Author(s):  
Lohith Bachegowda ◽  
Diptesh Gupta ◽  
Ajoy Bharadwaj ◽  
Karthik Ranganna ◽  
TIM Adamowicz ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Renal Transplant ◽  
Calcineurin Inhibitor ◽  
De Novo ◽  
Calcineurin Inhibitors ◽  
Solid Organ ◽  
Renal Transplant Recipients ◽  
Transplant Recipients ◽  
Hla Antigen ◽  
Post Transplant

Abstract Abstract 1683 Poster Board I-709 Introduction- Post-transplant malignancy is one of the major complications of immunosuppression in kidney transplant recipients. Mycophenolate Mofetil(MMF) and Calcineurin inhibitors(CNI) based immunosuppression is a well established combination in clinical practice. MMF has an action on cell proliferation by inhibiting Inosine Mono Phosphate dehydrogenase. However, its antitumor properties have been constantly debated. It is shown to have some antiproliferative effects in leukemias and lymphomas with a decreased incidence of PTLD. This single center study evaluated the effect of combining mycophenolate mofetil (MMF) with calcineurin inhibitors on the incidence of de novo post-transplant non skin malignancies in renal transplant recipients. We also compared the incidence of solid versus liquid cancers. Patients and Methods- Six hundred and fifty seven (657) consecutive kidney and kidney/pancreas recipients transplanted between January 2000 and December 2005 were analyzed for post-transplant malignancies. Three hundred and sixty two (362) recipients were maintained on a calcineurin inhibitor and MMF combination. The incidence of neoplasm in this group was monitored till June 2009. All patients received induction therapy with basiliximab and methylprednisolone. Steroid therapy was discontinued after the second dose in the withdrawal group. In the steroid treated group oral prednisone was initiated on day 2 at 30 mg per day and rapidly tapered to 5 mg per day at one month and continued for the life of the graft. Maintenance therapy in all recipients included both, a calcineurin inhibitor and mycophenolate mofetil (MMF). All clinical acute rejections were confirmed by biopsy and treated with intravenous methylprednisolone. Steroid unresponsive rejections were treated with Thymoglobulin Table 1 shows the demography in the CNI + MMF recipient group Recipient demography Calcineurin inhibitor/MMF group Number of recipients 362 Mean age in years 53 ± 3 Male gender 196 Deceased donor kidney recipients 305 Mean HLA antigen mismatch 3.95 ± 2.6 Pre-transplant malignancies 0 Number of recipients with rejection 71 Table 2 Incidence and type of malignancies in calcineurin inhibitor + MMF group Type of cancer Calcineurin inhibitor/MMF group Total number of recipients 362 Post transplant lymphoproliferative disease 1 Hodgkin's lymphoma 1 Renal cell cancer 6 Lung cancer 3 Prostate cancer 2 Colon cancer 2 Breast cancer 2 Bladder cancer 1 Pancreatic cancer 1 Leukemia 1 Thyroid cancer 1 Total cancers 21 (5.8%) Conclusion In our study on CNI/MMF based immunosuppression in renal transplant patients, 5.8% developed various neoplasms. There was a lower incidence of hematologic- malignancies 3/362(0.8%) in comparison to solid organ neoplasm 18/362(4.97%). The incidence of PTLD was 0.27%, which is similar to other observational studies. This could partly be due to greater expression of Inosine Monophosphate, inhibited by MMF in malignant hematologic cells. Further multicenter analysis needs to be done to detect the incidence of liquid and solid neoplasms, correlating with intracellular IMP levels with MMF usage in renal transplant recipients. Disclosures No relevant conflicts of interest to declare.

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